Cancer threatens the lives of all human beings greatly. According to the statistics from the WHO, cancer kills an estimated 5 million people around the world every year, so the prevention and therapy for cancer are onerous tasks. The drug therapy is one of three main therapies for cancer. The conventional therapies for malignant tumours by chemical drugs focus on killing tumour cells directly or indirectly, resulting in certain lethality to normal cells, obvious toxic and side effects, and great restriction to such cytotoxic drugs in therapeutic effect and application due to the drug resistance of the tumour cells. Since Friend, et al., discovered that mouse erythroleukemia cells induced by DMSO can be differentiated to synthesize hemoglobin in 1971, people have gradually recognized that malignant cells can be ‘reversed’ by using differentiation inducers to return to normal cells, which arouses the interest and attention of scholars. With the in-depth research on tumour pathogenesis, the induction of differentiation therapy has become a new breakthrough in the tumour therapeutics. The induction of differentiation is a phenomenon that malignant tumour cells, under the actions of differentiation inducers in vitro and in vivo, differentiate and reverse to normal cells or close to normal cells. This therapy focuses on returning the tumours back rather than killing them directly, thereby curing them finally. The discovery of effective differentiation inducers will change the former treatment modes of mainly killing the tumour cells, and form a new therapy of mainly controlling and adjusting the biological behaviours of the tumour cells, thereby implementing the cure of tumours finally. Particularly in recent 20 years, with the tremendous development of molecular biology of tumour and its technology, scientists have achieved fruitful outcomes in the field of drug research on inducing malignant tumour cells to differentiate and discovered hundreds of compounds with differentiation functions, many of which have been in the clinic tests of stages I and II and a few of which, such as retinoic acid, have been used as differentiation inducers for the clinic tumour treatment and prevention, with certain therapeutic effect, therefore, the research and application of differentiation inducers open a wide way for tumour drugs and their pharmaceutical research.
Retinoic acid and retinoids thereof are a range of vitamin A derivatives of over 4000 kinds, including retinoic acid, vaminic acid, viaminate, natural vitamin A, etc. Retinoid compounds are widely used for the therapy of skin disorders, such as keratosis and photoage, however, remarkably for the prevention and therapy of some malignant tumours, such as mammary cancer, skin cancer, cervical cancer and leukaemia. Scientific researchers widely and deeply research all-trans retinoic acid and 9-cis retinoic acid of such compounds. The two compounds have the functions of resisting keratosis and hyperplasia and improving the normal differentiation of epidermal cells by involving in the proliferation and differentiation of regulatory cells, interfering the occurrence of tumours by inhibiting the activity of ornithine dehydrogenase, and are capable of directly inhibiting the synthesis of sebum and the proliferation of sebaceous gland cells to reduce the secretion of sebum (You Lei, Yan Huanglin, Retinoid Compounds and Receptors Thereof and Research Development of Psoriasis; Medical Recapitulate 2007, 13 (06), 466-467). Since 1988, Shanghai Retinoic Acid Association first used all-trans retinoic acid (ATRA) for the induction of differentiation therapy of human acute promyelocytic leukaemia with remarkable therapeutic effect and complete remission rate of 86% based on 5-year clinic summary. At present, ATRA has been used in the treatment of malignant tumours, such as acute promyelocytic leukaemia and oral leukoplakia and become one of the preferred drugs for the treatment of leukaemia (Evans T R, Kaye S B. Br J Cancer, 1999, 80 (1-2): 1-9) 9-cis retinoic acid has the therapeutic effect equivalent to that of ATRA but less side effect, hopefully used as a clinic drug. The structures of common retinoid compounds are as follows:

However, with increasingly wide application of retinoic acid, the untoward effects occurred often caused by ATRA are as follows: 1, damage of skin and mucous membrane; 2, untoward effects of digestive system with high incidence rate, such as nausea, vomiting, anorexia and distended upper abdomen; 3, untoward effects of nervous system, such as headache, papilledema and increased cerebrospinal pressure, during the treatment of patients by ATRA; 4, untoward effects of bone, joint and muscle normally caused by ATRA; 5, increased leukocyte count with the incidence rate of about 30% during the treatment of APL by ATRA, reported abroad; and, 6, retinoic acid syndrome (RA-RS), the main danger during the treatment of APL by ATRA, with the main manifestations of fever and difficulty in breathing and other symptoms and physical signs of increased weight, distal limb edema, hydrothorax or pericardial effusion, and paroxysmal hypotension and pulmonary interstitial infiltration seen from chest radiograph. In addition, ATRA can cause carpal tunnel syndrome, serious heart damage, hyperlipidemia, hyperammonemia and other untoward effects (Zhao Huanyu; Untoward Effects of All-trans Retinoic Acid; Chinese Pharmaceutical Journal 1998 33 (7): 440-441), greatly limiting the application of drugs. Meanwhile, fast developed drug resistance and high recurrence rate are still two obstacles affecting the long-term therapeutic effect. With the further application in clinic, people found that ATRA can form drug resistance and make the remission of patients suffering recurrence more difficult. Thus, it is necessary to improve the therapeutic effect, widen the clinic application range and reduce the untoward effect of drugs. Therefore, a great number of structure modification jobs for the retinoid drugs are carried out home and abroad.
Xu Shiping, et al., designed and synthesized a series of retinoic acid derivatives for improving the performance of retinoid compounds (Acta Pharmaceutica Sinica (1981), 16 (9), 678-86), in which viaminate (RI) and vaminic acid (RII) have better effects in anti-carcinogenesis and the like, with lower toxicity, thereby being suitable for the cancer chemoprophylaxis and the treatment of precancerous lesion. Du Congzhi, et al., found that viaminate (RI) and vaminic acid (RII) have low toxicity, compared with the toxicities of retinoid compounds, such as viaminate (RI), vaminic acid (RII), retinoic acid, etretinate and isotretinoin, which indicates that they are suitable for the application of the treatment of precancerous lesion (Acta Pharmaceutica Sinica 17: 333-337 (1982)). An invention, application No.: 97116602.1, discloses a retinamide coumarin compound and preparation method thereof and pharmaceutical compositions having the same.
There are also lots of reports related to the research on retinoids abroad. For example, isotretinoin and acitretin have been in the market as skin drugs. The structure modification of terminal polar groups of retinoic acid is focused on the oxyacylation and azoacylation. For example, Kyoko Nakagawa-Goto, et al., adopted the condensate of retinoic acid and taxane for enhancing the therapeutic effect of drugs (Kyoko Nakagawa-Goto, Koji Yamada, et al., Antitumor agents. 258. Syntheses and evaluation of dietary antioxidant-taxoid conjugates as novel cytotoxic agents, Bioorganic & Medicinal Chemistry Letters 17 (2007) 5204-5209), and, Gholam H. Hakimelahi, et al., used monoclonal antibodies capable of combining with the specificities of surface antigens of tumour cells as carriers to transport β-lactamase, after which the retinoic acid prodrug (a compound obtained by connecting ATRA to the C-3 position of a cephalosporin) was administrated and catalyzed by the β-lactamase at the tumour cells to release pharmacophoric groups in the C-3 position, thereby selectively killing the tumour cells. In-vitro experiment found that the joint use of the compound (5) and β-lactamase has greater inhibition to the proliferation of mammary cancer tumour cell MCF7 than that of the compound (5) (Hakimelahi G H, Ly T W, Yu S F, et al. Design and synthesis of a cephalosporin-retinoic acid prodrug activated by a monoclonal antibody-β-lactamase conjugate [J]. Bioorg Med Chem, 2001, 9(8): 2139-2147). Stefano Manfredini, et al., covalently condensed retinoic acid with Ara-A, Ara-C and 3 (2H)-Furanone, in which some compounds have strong inhibition to the growth of cells (Stefano Manfredini, Daniele Simoni, Roberto Ferroni, et al. Retinoic Acid Conjugates as Potential Antitumor Agents: Synthesis and Biological Activity of Conjugates with Ara-A, Ara-C, 3 (2H)-Furanone, and Aniline Mustard Moieties, J. Med. Chem. 1997, 40, 3851-38), but the modifications to these structures are to joint the corresponding drugs and exert the functions of the drugs, with the defects of large molecular weight and uncertain stability and drug targets due to the joint of two drugs, thereby possibly not being used for drug application. So micromolecular compounds ought to be used as substrates for terminal carboxyl acylation.
U.S. Pat. No. 4,190,594 discloses esterification and amidation of a series of retinoic acids for the prevention and treatment of the damage caused by UV irradiation, in which, fenretinide (4-HPR), is often used for the treatment of various skin disorders and currently as a drug for the prevention and treatment of many tumours for the evaluation (Soo-Jong U M, a Youn-Ja KWON, et al. Synthesis and Biological Activity of Novel Retinamide and Retinoate Derivatives, Chem. Pharm. Bull. 52 (5)501-506 (2004)). Fenretinide (4-HPR) is the selective agonist for RAR-β and RAR-γ. According to the researches in recent years, fenretinide is different from the conventional retinoid compounds that it has weaker induction of differentiation, strong action of improving the apoptosis of tumour cells, and lower toxicity than other retinoid compounds, for long-term use with low incidence rate of drug resistance and for single or joint use with other chemical therapy drugs for anti-tumour. In recent years, some researches abroad showed that fenretinide has the direct inhibition effect to many different solid tumours and has been in the stage of clinic experiment, with incomplete known anti-tumour action mechanisms. The present researches found that the possible mechanisms of fenretinide include proliferation inhibition to tumour cells, differentiation improvement, apoptosis initiation and influence on other signalling pathways, and the apoptosis-inducing biochemical pathway of fenretinide is so complex. Meanwhile, retinoic acid receptor dependence and retinoic acid receptor independence were reported, and the latter can improve the generation of reactive oxygen species (ROS) and neuropeptide, etc. In addition, the fenretinide can inhibit angiogenesis and HIV, resist rheumatism, treat psoriasis and the like. Therefore, fenretinide becomes one focus in the current research. But, during the clinic application, its main disadvantage is low bioavailability. The researches indicated that, when the dosage of a patient is 200 mg/day, the plasma concentration of the patient is lower than 1 μM, while the effective concentration required to generate apoptosis in vivo is 101 μM, therefore, it is necessary to increase the administration dosage or synthesize derivatives with better clinic effect. The recently synthesized derivatives are obtained by hydroxylation and carboxylation or methoxy-substitution and the like to the aniline structure. But only partial compounds in these derivatives show better bioactivities (Clifford J. L., Sabichi A. L., Zou C., Yang X., Steele V. E., Kelloff G. J., Lotan R., Lippman S. M., Cancer Epidemiol. Biomarkers Prev., 10, 391-395 (2001); Sun S. Y., Yue P., Kelloff G. J., Steele V. E., Lippman S. M., Hong W. K., Lotan R., Cancer Epidemiol. Biomarkers Prey., 10, 595-601 (2001)). Soo-Jong U M, et al., modified the structure of 4-HPR and obtained a series of compounds having high cytotoxicity and better water solubility. The main method is to bond sodium butyrate having anticancer activity to retinoic acid by p-aminophenol to generate 4-BPRE, a butyryl aminophenyl ester of retinoic acid. The molecular pharmacology experiment shows that the compound has the dual anti-tumour activities of sodium butyrate and retinoic acid both (Um S J, Kwon Y J, Han H S, et al. Synthesis and biological activity of novel retinamide and retinoate derivatives [J]. Chem Pharm Bull, 2004, 52 (5): 501-506; Um S J, Han H S, Kwon Y J, et al. In vitro antitumor potential of 4-BPRE, a butyryl aminophenyl ester of retinoic acid: role of the butyryl group [J]. Oncol Rep, 2004, 11 (3): 719-726).